Process for preparation of 2-aminotetralin derivatives and intermediates thereof

ABSTRACT

The present invention is to efficiently and simply prepare an optically active 7-substituted-2-aminotetralin with industrial advantage. In the process, a 7-substituted-2-tetralone or its bisulfite adduct is reduced with a microorganism to an optically active 7-substituted-2-tetralol. Then, a sulfonyl group is introduced to the hydroxy group to form an optically active 7-substituted-2-sulfonyloxytetralin. Then, with inversion of the configuration, a nitrogen substituent is introduced using a nitrogen nucleophile to form an optically active 2,7-substituted tetralin. Furthermore, if necessary, the nitrogen substituent is converted into a non-substituted amino group. Thus, an optically active 7-substituted-2-aminotetralin or its salt is prepared.

TECHNICAL FIELD

The present invention relates to processes for preparation of2-aminotetralin derivatives and their intermediates significantly usefulas synthesized intermediates of medicine, and to important intermediatesin the process. More specifically, the present invention relates toprocesses for preparing 7-substituted-2-tetralol by enzymically reducing7-substituted-2-tetralone and for deriving 7-substituted-2-aminotetralinfrom 7-substituted-2-tetralol, and to intermediates in the processes.

BACKGROUND ART

Optically active 2-tetralol derivatives and 2-aminotetralin derivativeshave been conventionally prepared by the following processes:

(Processes for preparing optically active 2-tetralol derivatives)

-   (1) The process of allowing bakers' yeast (Tetrahedron, Vol. 51, pp.    11,531-11,546, 1995), a microorganism of the genus Sporobolomyces    (Journal of Chemical Society, Parkin Transactions 1, pp. 3141-3144,    1992), or a microorganism of the genus Trichosporon (Journal of    Fermentation and Bioengineering, Vol. 81, pp. 304-309, 1996) to act    on a 2-tetralone derivative.    (Processes for preparing optically active 2-aminotetralin    derivatives)-   (2) The process (Japanese Unexamined Patent Application Publication    Nos. 11-228511 and 2000-7624) in which    (S)-N-methoxycarbonyl-p-methoxyhomophenylalanine acid chloride is    cyclized to (S)-N-methoxycarbonyl-7-methoxy-2-aminotetralin-1-one in    the presence of titanium tetrachloride; the ketone is reduced with    sodium borohydride to    (S)-N-methoxycarbonyl-7-methoxy-1-hydroxy-2-aminotetralin, followed    by allowing sodium hydride to act to form an optically active    oxazolidinone derivative; and finally the oxazolidinone derivative    is subjected to hydrogenolysis to yield    (S)-7-methoxy-2-aminotetralin.-   (3) The process in which a Schiff base synthesized from    7-methoxy-2-tetralone and (R)-phenethylamine is reduced with sodium    borohydride to (S)-N-phenethyl-7-methoxy-2-aminotetralin; the    product is subjected to hydrogenolysis to    (S)-7-methoxy-2-aminotetralin, followed by forming a diastereomeric    salt with mandelic acid; and then the salt is recrystallized to    increase the optical purity (Japanese Unexamined Patent Application    Publication No. 10-72411).-   (4) The process in which 6-bromo-2-tetralone is reduced with a    microorganism to (S)-6-bromo-2-tetralol; the hydroxyl group is    mesylated with mesyl chloride and replaced with sodium azide to form    an azide; then the azide is reduced with sodium borohydride and    cobalt bromide to (R)-6-bromo-2-aminotetralin (Journal of Organic    Chemistry, Vol. 60, p. 4324, 1995).

However, in process (1), the optical purity of the resulting compound islow and the microorganism has low capability of transforming thesubstrate. Therefore, this process does not necessarily lead tosatisfactory results. Process (2) has relatively large number of steps,and requires another several steps to synthesize the starting material(S)-N-methoxycarbonyl-p-methoxyhomophenylalanine. In addition, theprocess needs to use titanium tetrachloride or chlorobenzene, whichrequire careful handling, in the step of Friedel-Crafts cyclization andsodium hydride, which also require careful handling, in the step offorming oxazolidinone. In process (3), the resulting targeted compoundhas a low optical purity. Accordingly, the optical purity must beincreased by separation with mandelic acid. Thus, the process iseconomically inefficient. Process (4) is simple and thus relativelyfavorable. However, the process uses expensive sodium borohydriderequiring careful handling. In the step of reducing the azido group toan amino group, applying a simple hydrogenolysis causes the bromine atomsubstituted on the benzene ring to be hydrogenated undesirably. Thepresent invention does not need to take into account thesedisadvantages.

Thus, any process in the known art has problems to be overcome. In viewof the above-described circumstances, the object of the presentinvention is to provide an efficient, economical, industriallyadvantageous process for preparing 2-aminotetralin derivatives and toprovide important intermediates of the 2-aminotetralin derivatives.

SUMMARY OF INVENTION

The inventors have conducted research to overcome the problems byvarious approaches and, consequently accomplished the present invention.

Specifically, the present invention relates to a process for preparingan optically active 7-substituted-2-tetralol (2). In the process, a7-substituted-2-tetralone or its bisulfite adduct is reduced with aculture broth of microorganism, cell, or a material derived therefromcapable of transforming the 7-substituted-2-tetralone or its bisulfiteadduct into the optically active 7-substituted-2-tetralol, wherein themicroorganism is a microorganism belonging to a genus selected from thegroup consisting of Candida, Debaryomyces, Pichia, Kluyveromyces,Metschnikowia, Ogataea, Sporidiobolus, Torulaspora, Geotrichum,Yamadazyma, Endomyces, Dipodascus, Saccharomycopsis, Issatchenkia,Kuraishia, Lipomyces, Lodderomyces, Rhodosporidium, Rhodotorula,Sporobolomyces, Saturnispora, Zygosaccharomyces, Cellulomonas, Jensenia,Arthrobacter, Acidiphilium, Pseudomonas, Rhodococcus, Devosia, andMicrococcus. The 7-substituted-2-tetralone is expressed by generalformula (1):

(wherein R₁ represents hydrogen, an alkyl group having 1 to 10 carbonatoms, an aryl group having 6 to 20 carbon atoms, or an aralkyl grouphaving 7 to 20 carbon atoms). The optically active7-substituted-2-tetralol is expressed by general formula (2):

(wherein R₁ represents the same as above, and * represents an asymmetriccarbon atom).

The present invention also relates to a process for preparing anoptically active 7-substituted-2-aminotetralin or a salt thereof. In theprocess, a sulfonyl group is introduced to the hydroxy group of anoptically active 7-substituted-2-tetralol to form an optically active7-substituted-2-sulfonyloxytetralin. The optically active7-substituted-2-tetralol is expressed by general formula (2):

(wherein * represents an asymmetric carbon atom and R₁ representshydrogen, an alkyl group having 1 to 10 carbon atoms, an aryl grouphaving 6 to 20 carbon atoms, or an aralkyl group having 7 to 20 carbonatoms). The optically active 7-substituted-2-sulfonyloxytetralin isexpressed by general formula (3):

(wherein * and R₁ represent the same as above, and R₂ represents analkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20carbon atoms, an aralkyl group having 7 to 20 carbon atoms, asubstituted amino group, or a hydroxy group). Then, a nitrogensubstituent is introduced using a nitrogen nucleophile to form anoptically active 2,7-substituted tetralin with inversion of theconfiguration. The optically active 2,7-substituted tetralin isexpressed by general formula (4):

(wherein * and R₁ represents the same as above, and X represents anon-substituted amino group, an alkylamino group having 1 to 10 carbonatoms, an arylamino group having 6 to 20 carbon atoms, an aralkylaminogroup having 7 to 20 carbon atoms, an amido group having 1 to 20 carbonatoms, an imido group having 2 to 20 carbon atoms, a sulfonylamino grouphaving 1 to 20 carbon atoms, or an azido group). Furthermore, ifnecessary, the nitrogen substituent is transformed to a non-substitutedamino group. The resulting optically active7-substituted-2-aminotetralin is expressed by general formula (5):

(wherein * and R₁ represents the same as above).

The present invention also relates to an optically active7-substituted-2-sulfonyloxytetralin expressed by general formula (3):

(wherein * represents an asymmetric carbon atom, and R₁ representshydrogen, an alkyl group having 1 to 10 carbon atoms, an aryl grouphaving 6 to 20 carbon atoms, or an aralkyl group having 7 to 20 carbonatoms, and R₂ represents an alkyl group having 1 to 10 carbon atoms, anaryl group having 6 to 20 carbon atoms, an aralkyl group having 7 to 20carbon atoms, a substituted amino group, or a hydroxy group).

DISCLOSURE OF INVENTION

The present invention will be further described in detail.

First, a process for converting a 7-substituted-2-tetralone (1) into anoptically active 7-substituted-2-tetralol (2) by microbial reductionwill be described.

In the 7-substituted-2-tetralone (1) used in the present invention, R₁represents hydrogen, an alkyl group having 1 to 10 carbon atoms, an arylgroup having 6 to 20 carbon atoms, or an aralkyl group having 7 to 20carbon atoms.

The alkyl group having 1 to 10 carbon atoms, the aryl group having 6 to20 carbon atoms, and the aralkyl group having 7 to 20 carbon atoms mayhave a substituent, such as a halogen, an alkyl group having 1 to 10carbon atoms, or a nitro group.

For example, alkyl groups having 1 to 10 carbon atoms include methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, andtrifluoromethyl. Among these, the methyl group is preferable because itcan be deprotected in a downstream step. For example, aryl groups having6 to 20 carbon atoms include phenyl, p-methylphenyl, o-nitrophenyl,m-nitrophenyl, p-nitrophenyl, 2,4-dinitrophenyl, and p-chlorophenyl. Thearalkyl group having 7 to 20 carbon atoms is, for example, a benzylgroup.

Particularly preferably, R₁ is the methyl group.

The description of R₁ is applied to general formulas (2) to (5).

In the description herein, * represents an asymmetric carbon atom.

If the 7-substituted-2-tetralone (1) is, for example,7-methoxy-2-tetralone, it can be synthesized by reducing easilyavailable 2,7-dimethoxynaphthalene by Birch reduction (TetrahedronLetters, Vol. 31, p. 875 (1990)).

In the present invention, a bisulfite adduct of the7-substituted-2-tetralone (1) may be used in the same manner. Thebisulfite adduct can be prepared by treating the7-substituted-2-tetralone (1) with a bisulfite. Since the bisulfiteadduct is of crystalline solid, it is superior in stability andworkability to carbonyl compounds and is often easy to use accordingly.

For example, bisulfites used in the treatment above include potassiumbisulfite, sodium bisulfite, and calcium bisulfite. Preferably, sodiumbisulfite is used.

The treatment is carried out by using water or a mixed solventcontaining water and an organic solvent miscible with water andnonreactive with the bisulfite. A solution of the bisulfite may be addedto a solution of the 7-substituted-2-tetralone (1), or the solution ofthe 7-substituted-2-tetralone (1) may be added to the bisulfitesolution. Exemplary solvents miscible with water and nonreactive withthe bisulfite include, but not limited to, 1,2-dimethoxyethane,1,4-dioxane, tetrahydrofuran, diethylene glycol dimethyl ether,triethylene glycol dimethyl ether, polyethylene glycol dimethyl ether,acetonitrile, methanol, ethanol, n-propanol, isopropanol, and t-butanol.

The bisulfite is used in an amount in the range of, for example, 1 to100 equivalents relative to the 7-substituted-2-tetralone (1) normally,but the amount depends on the types of metal salt and solvent used andtreating conditions. Preferably, the lower limit is 1 equivalent and theupper limit is 20 equivalents, and more preferably the lower limit is 1equivalent and the upper limit is 10 equivalents, from the viewpoint ofeconomical efficiency.

The microorganism for converting the 7-substituted-2-tetralone (1) intothe optically active 7-substituted-2-tetralol (2) may be selected by,for example, the following process.

First, microbial cells are collected from 5 mL of a culture broth of amicroorganism by centrifugation or the like and suspended in 1 mL of a100 mM phosphate buffer solution (pH 6.5) containing 5 mg of7-methoxy-2-tetralone and 5 mg of glucose. The suspension is shaken in atest tube at 30° C. for 2 to 3 days. For evaluation of the reductioncapability, for example, the reaction mixture after the shaking reactionis subjected to extraction with ethyl acetate, and optically active7-methoxy-2-tetralol produced in the extract is analyzed byhigh-performance liquid chromatography. If the optically active7-methoxy-2-tetralol is produced, the microorganism is accepted.

The microorganism used in the present invention is selected on the basisof satisfactory results of the above-described test from among bacteria,actinomycete, mold, yeast, and fungi imperfecti. In particular, amicroorganism is preferably used which belongs to a genus selected fromthe group consisting of Candida, Debaryomyces, Pichia, Kluyveromyces,Metschnikowia, Ogataea, Sporidiobolus, Torulaspora, Geotrichum,Yamadazyma, Endomyces, Dipodascus, Saccharomycopsis, Issatchenkia,Kuraishia, Lipomyces, Lodderomyces, Rhodosporidium, Rhodotorula,Sporobolomyces, Saturnispora, Zygosaccharomyces, Cellulomonas, Jensenia,Arthrobacter, Acidiphilium, Pseudomonas, Rhodococcus, Devosia, andMicrococcus. Among these genera, Candida, Sporidiobolus, Yamadazyma,Acidiphilium, Pseudomonas, and Devosia are more preferable.

For a 7-substituted-2-tetralol in an (R) form, preferred microorganismsbelong to a genus selected from the group consisting of Candida,Debaryomyces, Pichia, Kluyveromyces, Metschnikowia, Ogataea,Sporidiobolus, Torulaspora, Geotrichum, Yamadazyma, Arthrobacter,Acidiphilium, Pseudomonas, Rhodococcus, and Devosia. Among these genera,Candida, Sporidiobolus, Yamadazyma, Acidiphilium, Pseudomonas, andDevosia are more preferable. Specifically, for example, microorganismsinclude Candida magnoliae IFO705, Candida maris IFO10003, Candidacatenulate IFO0745, Candida glabrata IFO0005, Candida maltosa IFO1976,Candida albicans IFO1594, Candida fennica CBS6087, Debaryomyces hanseniivar. hansenii IFO0019, Pichia anomala IFO0118, Kluyveromyces polysporusIFO0996, Metschnokowia bicuspidata var. bicuspidata IFO1408,Ogataeaminuta var. nonfermentans IFO1473, Sporidiobolus johnsoniiIFO6903, Tolulaspora delbrueckii IFO0381, Geotrichum fermentans IFO1199,Yamadazyma farinosa IFO0534, Arthrobacter protophormiae IFO12128,Acidiphilium cryptum IFO 14242, Pseudomonas putida IFO14164, Rhodococcuserythropolis IFO12320, and Devosia riboflavina IFO13584.

For a 7-substituted-2-tetralol in an (S) form, preferred microorganismsbelong to a genus selected from the group consisting of Candida,Debaryomyces, Endomyces, Dipodascus, Saccharomycopsis, Issatchenkia,Kuraishia, Lipomyces, Lodderomyces, Pichia, Rhodosporidium, Rhodotorula,Sporobolomyces, Sporidiobolus, Saturnispora, Zygosaccharomyces,Cellulomonas, Jensenia, Micrococcus, Rhodococcus, and Metschnikowia.Among these genera, Candida, Debaryomyces, Dipodascus, and Rhodococcusare more preferable. Specifically, exemplary microorganisms includeCandida glaebosa IFO1353, Candida haemulonii IFO10001, Candida holmiiIFO0660, Candida intermedia IFO0761, Candida boidinii IFO10240, Candidapintolopesii IFO0729, Candida oleophila IFO1021, Candida sonorensisIFO10027, Candida tropicalis IFO0618, Debaryomyces carsonii IFO0946,Endomyces decipiens IFO0102, Dipodascus ovetensis IFO1201,Saccharomycopsis selenospora IFO1850, Issatchenkia terricola IFO0933,Kuraishia capsulate IFO0721, Lipomyces starkeyi IFO0678, Lodderomyceselongisporus IFO1676, Metschnikowia gruessii IFO0749, Pichia wickerhamiiIFO1278, Rhodosporidium toruloides IFO0559, Rhodotorula araucariaeIFO10053, Sporobolomyces salmonicolor IFO1038, Sporidiobolus holsaticusIFO1032, Debaryomyces occidentalis var. occidentalis IFO0371,Saturnispora dispora IFO0035, Candida stellata IFO0703,Zygosaccharomyces bailli IFO0519, Zygosaccharomyces bailli IFO0488,Zygosaccharomyces bailii IFO0493, Cellulomonas fimi IFO15513, Jenseniacanicruria IFO13914, Micrococcus luteus IFO13867, and Rhodococcuserythropolis IAM1474.

These microorganisms can be obtained from stock strains readilyavailable or purchasable or can be isolated from the natural world. Itis also possible to obtain strains having favorable properties for thereaction by causing mutation of these microorganisms.

In culturing these microorganisms, any of the media containing nutrientsources assimilable by these microorganisms can generally be used. Forexample, used are ordinary media prepared by mixing and incorporatingcarbon sources, for example, saccharide, such as glucose, sucrose, andmaltose, organic acids such as lactic acid, acetic acid, citric acid,and propionic acid, alcohols such as ethanol and glycerin, hydrocarbonssuch as paraffins, fats and oils such as soybean oil and rapeseed oil,or mixtures of these; nitrogen sources such as ammonium sulfate,ammonium phosphate, urea, yeast extract, meat extract, peptone, and cornsteep liquor, and, further, other nutrient sources, for example, otherinorganic salts and vitamins.

The culture broth of the microorganism can be generally carried outunder ordinary conditions, preferably at a pH of 4.0 to 9.5 and atemperature within the range of 20° C. to 45° C., more preferably at apH of 5 to 8 and a temperature within the range of 25 to 40° C., underaerobic conditions for 10 to 96 hours, for instance.

In the reaction of the microorganism with the 7-substituted-2-tetralone(1), the culture broth containing cells of the above microorganisms canbe generally used as it is. The culture broth may also be used in aconcentrated form. In cases a certain component in the culture brothadversely affect the reaction, preferably, microbial cells or a materialderived therefrom obtained by centrifugation of the culture broth mayalso be used.

The material derived from cells of the microorganism is not particularlylimited, but includes dried cells obtained by dehydration treatment withacetone or diphosphorus pentaoxide or by drying using a desiccator orelectric fan, materials derived by surfactant treatment, materialsderived by lytic enzyme treatment, immobilized cells, and cell-freeextract preparations derived from disruption of cells. It is alsopossible to use an enzyme catalyzing enantioselective reductionreaction, purified from a culture broth.

In the reduction reaction, the substrate 7-substituted-2-tetralone orits bisulfite adduct may be added all at once in an early stage of thereaction or in divided portions with the progress of the reaction.

The temperature during the reaction is generally 10 to 60° C., andpreferably 20 to 40° C., and the pH during the reaction is within therange of 2.5 to 9, preferably 5 to 9.

The content of the culture broth of microorganism, cell, or a materialderived therefrom (hereinafter referred to as the culture broth or thelike of the microorganism) in the reaction mixture can be appropriatelyselected according to the ability thereof to reduce the substrate.

The concentration of the substrate in the reaction mixture is preferably0.01% to 50% (w/v), more preferably 0.1% to 30% (w/v).

The above reaction is generally carried out with shaking or withaeration and stirring. The reaction time is appropriately selectedaccording to the concentrations of the substrate and the culture brothor the like of the microorganism and other reaction conditions. Ingeneral, it is preferable to select such reaction conditions that thereaction is completed in 2 to 168 hours.

For promoting the reduction reaction, the addition, in an amount of 1%to 30% (w/v), of an energy source, such as glucose or ethanol, ispreferable to obtain better results.

The reaction can also be promoted by adding a coenzyme generallyrequired for biological reduction reaction, and such coenzymes includereduced nicotinamide adenine dinucleotide (NADH) and reducednicotinamide adenine dinucleotide phosphate (NADPH). Specifically, thecoenzyme may be directly added to the reaction mixture, or a reactionsystem producing NADH or NADPH may be added together with an oxidizedcoenzyme. For example, such reaction systems include those which reduceNAD to NADH when formic acid dehydrogenase produces carbon dioxide andwater from formic acid, and those which reduce NAD to NADH or NADP toNADPH when glucose dehydrogenase produces gluconolactone from glucose.

It is also effective to add a surfactant, such as Triton (produced byNacalai Tesque), Span (produced by Kanto Kagaku), or Tween (produced byNacalai Tesque), to the reaction mixture.

In order to prevent the substrate and/or alcohol produced by thereduction reaction from inhibiting the reaction, a water-insolubleorganic solvent, such as ethyl acetate, butyl acetate, isopropyl ether,or toluene, may also be added to the reaction mixture. Furthermore, inorder to increase the solubility of the substrate, a water-solubleorganic solvent may be added, such as methanol, ethanol, acetone,tetrahydrofuran, or dimethylsulfoxide.

The optically active 7-substituted-2-tetralol (2) produced by thereduction may be extracted with a solvent, such as ethyl acetate ortoluene, directly or after separation of cells and so on, and thesolvent is removed to collect the compound. Additional purification by,for example, silica gel column chromatography or recrystallization canincrease the purity of the compound.

In the subsequent step, a sulfonyl group is introduced to the hydroxygroup of the optically active 7-substituted-2-tetralol (2) to form anoptically active 7-substituted-2-sulfonyloxytetralin (3).

The optically active 7-substituted-2-sulfonyloxytetralin expressed bygeneral formula (3) is a new compound and it will be advantageously usedfor preparing 2-aminotetralin derivatives, which are useful as asynthesized intermediate of medicine.

R₂ represents an alkyl group having 1 to 10 carbon atoms, an aryl grouphaving 6 to 20 carbon atoms, an aralkyl group having 7 to 20 carbonatoms, a substituted amino group, or a hydroxy group. The alkyl grouphaving 1 to 10 carbon atoms, the aryl group having 6 to 20 carbon atoms,and the aralkyl group having 7 to 20 carbon atoms may have asubstituent, such as a halogen, an alkyl group having 1 to 10 carbonatoms, or a nitro group.

Exemplary alkyl groups having 1 to 10 carbon atoms include methyl,ethyl, and trifluoromethyl. Exemplary aryl groups having 6 to 20 carbonatoms include phenyl, p-methylphenyl, o-nitrophenyl, m-nitrophenyl,p-nitrophenyl, 2,4-dinitrophenyl, and p-chlorophenyl. The aralkyl grouphaving 7 to 20 carbon atoms is, for example, a benzyl group. Thesubstituted amino group is, for example, dimethylamino group.

Preferably, R₂ is methyl, phenyl, p-methylphenyl, o-nitrophenyl,m-nitrophenyl, or p-nitrophenyl from the viewpoint of increasing theyield of the subsequent substitution reaction.

For introducing a sulfonyl group to the optically active7-substituted-2-tetralol (2), a sulfonylating agent is used, such asmethanesulfonyl chloride, trifluoromethanesulfonyl chloride,benzenesulfonyl chloride, p-toluenesulfonyl chloride,o-nitrobenzenesulfonyl chloride, m-nitrobenzenesulfonyl chloride,p-nitrobenzenesulfonyl chloride, 2,4-dinitrobenzenesulfonyl chloride,p-chlorobenzenesulfonyl chloride, and dimethylaminosulfonyl chloride.Preferably, methanesulfonyl chloride, benzenesulfonyl chloride, orp-toluenesulfonyl chloride is used from the viewpoint of ease ofhandling and inexpensive availability.

The amount of sulfonylating agent is not particularly limited, but,normally, 1 mole equivalent or more of sulfonylating agent is usedrelative to the optically active 7-substituted-2-tetralol (2). Thepreferred amount is generally 10.0 mole equivalents or less, morepreferably 5.0 mole equivalents or less, and still more preferably 2.0mole equivalents or less, from the viewpoint of economical efficiency.

Since typical sulfonylation generates an acid in an amount equivalent tothat of the substrate in a mole basis, a base is added. Exemplary basesinclude: organic bases, such as triethylamine, pyridine,4-dimethylaminopyridine, and diisopropylethylamine; and inorganic bases,such as sodium hydroxide, sodium carbonate, and sodiumhydrogencarbonate. Among these bases, triethylamine and pyridine arepreferable from the viewpoint of yield and economical efficiency.

The amount of the base is not particularly limited, but, normally, 1mole equivalent or more of base is used relative to the optically active7-substituted-2-tetralol (2). The preferred amount is generally 10.0mole equivalents or less, more preferably 5.0 mole equivalents or less,and still more preferably 2.0 mole equivalents or less, from theviewpoint of economical efficiency. In particular, pyridine, which isvolatile, can be used as a solvent.

The reaction solvent used for the sulfonylation is not particularlylimited as long as it does not inhibit the reaction. Exemplary solventsinclude: hydrocarbon solvents, such as pentane, hexane, heptane,cyclohexane, and petroleum ether; esters, such as ethyl acetate, methylacetate, propyl acetate, and methyl propionate; aromatic hydrocarbons,such as toluene, benzene, and xylene; nitriles, such as acetonitrile andpropionitrile; ethers, such as tert-butyl methyl ether, diethyl ether,diisopropyl ether, tetrahydrofuran, and dioxane; ketones, such asacetone and ethyl methyl ketone; amides, such as N,N-dimethylformamideand N,N-dimethylacetamide; sulfoxides, such as dimethylsulfoxide;halogenated hydrocarbons, such as methylene chloride,1,2-dichloroethylene, chloroform, and carbon tetrachloride; and amines,such as pyridine and triethylamine. These solvents may be used singly orin combination. Among these, preferred solvents are toluene, ethylacetate, acetonitrile, dioxane, tetrahydrofuran, methylene chloride,1,2-dichloroethylene, and their mixture from the viewpoint of thesolubility of the optically active 7-substituted-2-tetralol (2) and thestability against the sulfonylating agent. In use of a mixed solvent,the mixing ratio is not particularly limited.

The concentration of the optically active 7-substituted-2-tetralol (2)in the sulfonylation depends on the reaction solvent used, but it isgenerally in the range of 1 to 50 percent by weight, and preferably inthe range of 5 to 30 percent by weight.

The temperature for the sulfonylation depends on the types ofsulfonylating agent and reaction solvent used, but it is generallybetween the freezing point and the boiling point of the reactionsolvent. In order to complete the reaction in short time, the reactionis performed at a higher temperature; in order to suppress sidereactions, the reaction is performed at a lower temperature. Thetemperature is generally in the range of −20 to 100° C., and morepreferably in the range of −10 to 30° C.

The reaction time for the sulfonylation depends on the types ofsulfonylating agent and reaction solvent used and reaction temperature,but it is generally in the range of 1 to 24 hours at a reactiontemperature in the range of −10 to 30° C.

After the sulfonylation, the sulfonylating agent is quenched with wateror an acid solution, such as that of hydrochloric acid or sulfuric acid.For a crystalline compound, such as a tosyl compound, however, thetargeted compound can be simply obtained by filtration because thecompound can be precipitated by adding water to the reaction solution.Otherwise, after the organic phase is separated, the organic phase iswashed several times with water or an acid solution to remove a base,and the solvent is evaporated under reduced pressure. Thus, theoptically active 7-substituted-2-sulfonyloxytetralin (3) is obtained.The optically active 7-substituted-2-sulfonyloxytetralin (3) may bepurified by silica gel chromatography, recrystallization, or the like ifnecessary.

In the subsequent step, a nitrogen nucleophile is allowed to act on theoptically active 7-substituted-2-sulfonyloxytetralin (3) to produce anoptically active 2,7-substituted tetralin (4). In this instance, theconfiguration of the compound is reversed from an (R) form to an (S)form or from an (S) form to an (R) form. It is preferred that the (S)form of optically active 2,7-substituted tetralin (4) is produced fromthe (R) form of optically active 7-substituted-2-sulfonyloxytetralin(3).

X of the optically active 2,7-substituted tetralin (4) expressed bygeneral formula (4) represents a non-substituted amino group, analkylamino group having 1 to 10 carbon atoms, an arylamino group having6 to 20 carbon atoms, an aralkylamino group having 7 to 20 carbon atoms,an amido group having 1 to 20 carbon atoms, an imido group having 2 to20 carbon atoms, a sulfonylamino group having 1 to 20 carbon atoms, oran azido group. Specifically, exemplary groups include the amino group;alkylamino groups having 1 to 10 carbon atoms, such as methylamino,ethylamino, and dimethylamino; aryl amino groups having 6 to 20 carbonatoms, such as phenylamino; aralkylamino groups having 7 to 20 carbonatoms, such as benzylamino; amido groups having 1 to 20 carbon atoms,such as acetylamino, diacetylamino, and diformylamino; imido groupshaving 2 to 20 carbon atoms, such as phthalimido; sulfonylamino groupshaving 1 to 20 carbon atoms, such as benzenesulfonylamino,p-nitrobenzenesulfonylamino, o-nitrobenzenesulfonylamino,m-nitrobenzenesulfonylamino, and p-toluenesulfonylamino; and the azidogroup. Among these groups, amino, phthalimido, and azido groups arepreferable from the viewpoint of increase in reaction yield and ease oftransformation into the amino group.

Exemplary nitrogen nucleophiles used for this reaction include amines,such as ammonia, methylamine, dimethylamine, benzylamine, and aniline;amides, such as acetylamide; imides, such as diacetylimide,diformylimide, phthalimide, and metal salts of phthalimide;sulfonylamides, such as benzenesulfonylamide,p-nitrobenzenesulfonylamide, o-nitrobenzenesulfonylamide,m-nitrobenzenesulfonylamide, and p-toluenesulfonylamide; and metalazides, such as sodium azide. Among these nucleophiles, ammonia, metalazides, and alkali metal salts of phthalimide are preferable from theviewpoint of increase in reaction yield and ease of transformation intothe amino group. In particular, if ammonia is used as the nitrogennucleophile, X of the product is the amino group, and the product isidentical with the optically active 7-substituted-2-aminotetralinexpressed by general formula (5). Therefore, it is unnecessary toperform the step of transforming X into the amino group, as a matter ofcourse.

In the process of the present invention, it is preferable that thenitrogen nucleophile is a metal azide and the X is an azido group, andthat the 2,7-substituted tetralin expressed by general formula (4) istransformed into the optically active 7-substituted-2-aminotetralinexpressed by general formula (5) or its salt by reduction. In thisreduction, hydrogen is preferably used.

The amount of nitrogen nucleophile depends on the types of nitrogennucleophile and solvent used. Normally, 1 mole equivalent or more ofnitrogen nucleophile is used relative to the optically active7-substituted-2-sulfonyloxytetralin (3). The preferred amount isgenerally 10.0 mole equivalents or less, more preferably 5.0 moleequivalents or less, and still more preferably 2.0 mole equivalents orless, from the viewpoint of economical efficiency. In particular, ifammonia is used as the nitrogen nucleophile, the amount of the nitrogennucleophile is preferably 10 mole equivalents or more, and morepreferably 50 mole equivalents or more, from the viewpoint of increasingthe yield. In view of economical efficiency, the amount is preferably300 mole equivalents or less, and more preferably 200 mole equivalentsor less.

The reaction solvent used for the substitution is not particularlylimited as long as it does not inhibit the reaction. Exemplary solventsinclude: hydrocarbon solvents, such as pentane, hexane, heptane,cyclohexane, and petroleum ether; esters, such as ethyl acetate, methylacetate, propyl acetate, and methyl propionate; alcohols, such asmethanol, ethanol, isopropanol, 1-butanol, and 2-butanol; aromatichydrocarbons, such as toluene, benzene, and xylene; nitriles, such asacetonitrile and propionitrile; ethers, such as tert-butyl methyl ether,diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, anddimethoxyethane; ketones, such as acetone and ethyl methyl ketone;amides, such as N,N-dimethylformamide and N,N-dimethylacetamide;sulfoxides, such as dimethylsulfoxide; halogenated hydrocarbons, such asmethylene chloride, 1,2-dichloroethylene, chloroform, and carbontetrachloride; amines, such as pyridine and triethylamine; and water.These solvents may be used singly or in combination. Among thesesolvents, preferred solvents are methanol, ethanol, isopropanol,1-butanol, 2-butanol, toluene, acetonitrile, tetrahydrofuran,dimethoxyethane, N,N-dimethylformamide, triethylamine, and mixturescontaining at least two of these solvents from the viewpoint of yield.If a mixed solvent is used, the mixing ratio is not particularlylimited. In use of ammonia as the nitrogen nucleophile, the substitutioncan proceed even without a reaction solvent.

The concentration of the optically active7-substituted-2-sulfonyloxytetralin (3) in the substitution reactiondepends on the reaction solvent used, but it is generally in the rangeof 1 to 50 percent by weight, and preferably in the range of 5 to 30percent by weight.

The temperature for the substitution reaction depends on the types ofnitrogen nucleophile and reaction solvent used, but it is generallybetween the freezing point and the boiling point of the reactionsolvent. In order to complete the reaction in short time, the reactionis performed at a higher temperature; in order to suppress sidereactions, the reaction is performed at a lower temperature. Thetemperature is generally in the range of 20 to 200° C., and morepreferably in the range of 50 to 150° C.

The reaction time for the substitution reaction depends on the types ofnitrogen nucleophile and reaction solvent used and reaction temperature,but it is generally in the range of 1 to 24 hours at a reactiontemperature in the range of 50 to 150° C.

If a nonaqueous solvent such as toluene or 1-butanol is used, after thesubstitution reaction, the organic phase is washed several times with aneutral or alkaline aqueous solution, and the solvent is evaporatedunder reduced pressure to obtain the optically active 2,7-substitutedtetralin (4). If a water-soluble solvent is used, such as methanol,dimethylformamide, tetrahydrofuran, or acetonitrile, the solvent isevaporated under reduced pressure, and the product is then dissolved inan organic solvent, such as ethyl acetate or toluene. After washing thesolution in the same manner, the solvent is evaporated under reducedpressure to obtain the optically active 2,7-substituted tetralin (4).

The substitution reaction often produces a β-eliminated3,4-dihydro-7-substituted naphthalene as a byproduct. However, thiscompound is oily in many cases. Accordingly, if the optically active2,7-substituted tetralin (4) is solid, the byproduct can be easilyremoved by crystallization. The optically active 2,7-substitutedtetralin (4) may be purified by silica gel chromatography or the like.

If the nitrogen nucleophile is ammonia, the targeted compound, opticallyactive 7-substituted-2-aminotetralin (5) is produced, as describedabove. The resulting compound (5) can be generally extracted into anorganic phase in the presence of an organic solvent and water at a pHfrom neutral to basic (pH 7 or more). The organic solvent is, forexample, toluene or ethyl acetate.

In order to remove impurities, the solution after the reaction or theabove-described extract may be neutralized with an acid to extract asalt of the optically active 7-substituted-2-aminotetralin (5) with theacid into a water phase. The water phase is washed with an organicsolvent, such as toluene or ethyl acetate. The resulting salt of theoptically active 7-substituted-2-aminotetralin (5) with the acid may beobtained in a solution or in a crystalline form. The salt can beconverted into a free amine and extracted with the above-describedsolvent to obtain an optically active 7-substituted-2-aminotetralin (5)as a free amine.

The resulting extract is, for example, heated under reduced pressure toevaporate the reaction solvent and the extractant, and thus theoptically active 7-substituted-2-aminotetralin (5) is obtained. Theoptically active 7-substituted-2-aminotetralin (5) thus produced issubstantially pure, but it may be purified to further increase thepurity by a conventional process, such as crystallization, distillation,or column chromatography.

For crystallizing the optically active 7-substituted-2-aminotetralin(5), normally, a salt of the compound with an acid is crystallized andisolated in a crystalline form. Preferably, the acid is, but not limitedto, a mineral acid, such as sulfuric acid, hydrogen chloride, orperchloric acid; or an organic acid, such as methanesulfonic acid orp-toluenesulfonic acid, and particularly preferred acid is hydrogenchloride.

The crystallization of the salt of the compound (5) with the acid isgenerally performed in the presence of a solvent. Exemplarycrystallization solvents include alcohols, such as methanol, ethanol,and propanol; and water. Using these solvents helps efficiently removeimpurities, such as optical isomers, the starting materials of theabove-described reactions, and compounds having a similar structureand/or a coloring substance. These solvents may be used singly or incombination. In order to increase the yield in the crystallization, anauxiliary solvent may be used in combination. Exemplary auxiliarysolvents include aromatic hydrocarbons, such as benzene, toluene,xylene, ethylbenzene, and chlorobenzene; esters, such as ethyl acetate,propyl acetate, and butyl acetate; ethers, such as diethyl ether andt-butyl methyl ether; nitrites, such as acetonitrile; aliphatichydrocarbons, such as hexane, pentane, heptane, cyclohexane, andmethylcyclohexane.

For crystallizing the salt of the optically active7-substituted-2-aminotetralin (5) with an acid, the acid is added to theextract of the compound (5) or a mixture of the extract and theabove-described solvent to form the salt of the compound (5) with theacid, and the salt is crystallized. Alternatively, the salt of thecompound (5) with the acid is recrystallized in the presence of thesolvent.

As described above, the use of ammonia as the nitrogen nucleophiledirectly produces the optically active 7-substituted-2-aminotetralin(5). However, use of other nitrogen nucleophiles requires the step oftransforming the substituent X of the optically active 2,7-substitutedtetralin (4) into the amino group. The reaction process in this stepdepends on the type of nitrogen nucleophile used, as a matter of course.

In use of a metal salt of phthalimide as the nitrogen nucleophile, thesubstituent X of the optically active 7,2-substituted tetralin (4) isthe phthalimide group. The phthalimide group is transformed into theamino group by deprotection to obtain the optically active7-substituted-2-aminotetralin (5). The deprotection may be performed byhydrolysis using hydrochloric acid, sulfuric acid, or the like, or byadding hydrazine.

In use of a metal azide as the nitrogen nucleophile, the substituent Xof the optically active 7,2-substituted tetralin (4) is the azido group.The azido group is transformed into the amino group by reduction toobtain the optically active 7-substituted-2-aminotetralin (5). Thisreduction reaction will now be described below, but it is not limited tothis.

Exemplary reducing agents used in this reduction include hydrogen-typeagents, such as hydrogen and ammonium formate; phosphorus-type agents,such as triphenylphosphine and trimethyl phosphite; hydrido agents, suchas sodium borohydride, borane, and lithium aluminiumhydride.

If hydrogen is used as the reducing agent, a transition metal catalystis necessary. Such transition metal catalysts include palladium/carbon,palladium black, palladium oxide, palladium/calcium carbonate, platinum,and platinum oxide.

The amount of the transition metal catalyst depends on the type oftransition metal used. Normally, 1 percent by weight or more of thecatalyst is used relative to the optically active 2,7-substitutedtetralin (4). As the amount is increased, the reaction rate increases.However, the preferred amount is generally 100 percent by weight orless, more preferably 30 percent by weight or less, and still morepreferably 10 percent by weight or less, from the viewpoint ofeconomical efficiency.

The hydrogen pressure is set between, for example, normal pressure and10 kg/cm². Although the pressure may be set high to increase thereaction rate if necessary, the reaction often proceeds rapidly atnormal pressure.

The reaction solvent used for the reduction reaction is not particularlylimited as long as it does not inhibit the reaction. Exemplary solventsinclude: hydrocarbons, such as pentane, hexane, heptane, cyclohexane,and petroleum ether; esters, such as ethyl acetate, methyl acetate,propyl acetate, and methyl propionate; alcohols, such as methanol,ethanol, isopropanol, and 1-butanol; aromatic hydrocarbons, such astoluene, benzene, and xylene; nitriles, such as acetonitrile andpropionitrile; ethers, such as tert-butyl methyl ether, diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, and dimethoxyethane;ketones, such as acetone and ethyl methyl ketone; amides, such asN,N-dimethylformamide and N,N-dimethylacetamide; sulfoxides, such asdimethylsulfoxide; halogenated hydrocarbons, such as methylene chloride,1,2-dichloroethylene, chloroform, and carbon tetrachloride; and water.These solvents may be used singly or in combination. Among thesesolvent, preferred solvents are water, methanol, ethanol, isopropanol,1-butanol, toluene, acetonitrile, tetrahydrofuran, ethyl acetate, andmixtures containing at least two of these solvents from the viewpoint ofyield. If a mixed solvent is used, the mixing ratio is not particularlylimited.

The concentration of the optically active 2,7-substituted tetralin (4)in the reduction reaction depends on the reaction solvent used, but itis generally in the range of 1 to 50 percent by weight, and preferablyin the range of 5 to 30 percent by weight.

The temperature for the reduction reaction depends on the types ofreducing agent and reaction solvent used, but it is generally betweenthe freezing point and the boiling point of the reaction solvent. Inorder to complete the reaction in short time, the reaction is performedat a higher temperature; in order to suppress side reactions, thereaction is performed at a lower temperature. The temperature isgenerally in the range of −20 to 150° C., and more preferably in therange of −10 to 100° C.

The reaction time for the reduction reaction depends on the types ofreducing agent and reaction solvent used and reaction temperature, butit is generally in the range of 1 to 24 hours at a reaction temperaturein the range of 20 to 120° C.

After the reduction, the resulting optically active7-substituted-2-aminotetralin (5) can be obtained in the same manner asin the substitution reaction from the compound (3) to the compound (4).In addition, the compound (5) may be crystallized by forming a salt withan acid.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will now be further described in detail withreference to Examples, but the invention is not limited to the examples.

EXAMPLE 1 Preparation of (R)-7-methoxy-2-tetralol

In a 500 mL Sakaguchi flasks are placed 50 mL aliquots of 500 mL of aliquid culture medium (pH 7.0) containing 40 g of glucose, 3 g of anyeast extract, 6.5 g of diammonium hydrogen phosphate, 1 g ofdipotassium hydrogen phosphate, 0.8 g of magnesium sulfate heptahydrate,60 mg of zinc sulfate heptahydrate, 90 mg of iron sulfate heptahydrate,5 mg of copper sulfate pentahydrate, 10 mg of manganese sulfatetetrahydrate, and 100 mg of sodium chloride (per liter each). Eachaliquot was steamsterilized at 120° C. for 20 minutes. A loopful ofCandida magnoliae IFO705 was aseptically inoculated into the aliquot,followed by shaking to cultivate the microorganism at 30° C. for 24hours. After the cultivation, the culture broth was centrifuged tocollect cells, and the cells were suspended in 50 mL of a 100 mMphosphate buffer solution (pH 7.0). To the suspension were added 1 g of7-methoxy-2-tetralone and 5 g of glucose. While being stirred at 30° C.for 24 hours, the reaction mixture is allowed to react with the pHmaintained at 6.5 with an aqueous solution of 5 M sodium hydroxide.After the reaction had been completed, the reaction mixture wasextracted two times with 500 mL of ethyl acetate. The organic phase wasdried over anhydrous sodium sulfate. The anhydrous sodium sulfate wasremoved by filtration, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatographyto yield 900 mg of (R)-7-methoxy-2-tetralol (yield: 89%). The opticalpurity measured under the following conditions was 81% ee.

Column: Daicel Chiralcel OJ (registered trademark) (4.6 mm×250 mm);eluant:n-hexane/isopropanol=9/1; flow rate: 1 mL/min, detection: 210 nm;column temperature: 30° C.; elution time: 11 minutes for(R)-7-methoxy-2-tetralone, 14 minutes for (S)-7-methoxy-2-tetralone.

EXAMPLE 2 Preparation of (R)-7-methoxy-2-tetralol

Using a culture broth of Candida maris IFO10003 prepared in the cultureof Example 1 in precisely the same manner as in Example 1, cell reactionand extraction and purification of the product were performed in thesame manner to yield 900 mg of (R)-7-methoxy-2-tetralol. The opticalpurity was 76% ee.

EXAMPLE 3 Preparation of (R)-7-methoxy-2-methanesulfonyloxytetralin

(R)-7-methoxy-2-tetralol (87.8% ee) was separately synthesized accordingto Example 1, and 1.00 g of this compound was dissolved in 6 mL ofmethylene chloride. While this solution is cooled with ice, 1.35 g ofmethanesulfonyl chloride and 1.42 g of triethylamine were added to thesolution, and the mixture was stirred at the same temperature for 2hours. After being washed twice with 1 M hydrochloric acid, the reactionmixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and dried over anhydrous sodium sulfate. Then, the solvent wasevaporated under reduced pressure to yield 1.31 g of oil. The oil waspurified with a silica gel column (hexane/ethyl acetate=1/1) to yield1.06 g of the compound of the heading (yield: 74%).

¹H-NMR (CDCl₃) δ ppm: δ 2.10-2.20 (q, 2H), 2.76-3.02 (m, 2H), 3.02 (s,3H), 3.00-3.23 (m, 2H), 3.78 (S, 3H), 5.18 (m, 1H), 6.60 (s, 1H), 6.73(d, 1H), 7.02 (d, 1H).

EXAMPLE 4 Preparation of (R)-7-methoxy-2-p-toluenesulfonyloxytetralin

In 19 mL of pyridine was dissolved 1.01 g of (R)-7-methoxy-2-tetralol(87.8% ee). While the solution is cooled with ice, 2.42 g ofp-toluenesulfonyl chloride was added to the solution. The reactionmixture was allowed to stand at −20° C. for 16 hours and at 0° C. for 20hours. Ice-cold water was added to the reaction mixture, followed bystirring for 30 minutes. The product was extracted three times withethyl acetate. After being washed five times with 1 M hydrochloric acid,the organic phase was washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous sodium sulfate. Then, the solvent wasevaporated under reduced pressure to yield 1.84 g of oil. The oil waspurified with a silica gel column (hexane/ethyl acetate=6/4) to yield1.34 g of the compound of the heading (yield: 72%).

¹H-NMR (CDCl₃) δ ppm: δ 2.00 (q, 2H), 2.46 (s, 3H), 2.65-3.02 (m, 4H),3.78 (S, 3H), 4.93 (m, 1H), 6.50 (s, 1H), 6.70 (d, 1H), 6.96 (d, 1H),7.35 (d, 2H), 7.80 (d, 2H).

EXAMPLE 5 Preparation of(R)-7-methoxy-2-m-nitrobenzenesulfonyloxytetralin

In 19 mL of pyridine was dissolved 1.01 g of (R)-7-methoxy-2-tetralol(87.8% ee). While the solution was cooled with ice, 2.53 g ofm-nitrobenzenesulfonyl chloride was added to the solution. The reactionmixture was allowed to stand at −20° C. for 16 hours and at 0° C. for 20hours. Ice-cold water was added to the reaction mixture, followed bystirring for 30 minutes. The product was extracted three times withethyl acetate. After being washed five times with 1 M hydrochloric acid,the organic phase was washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous sodium sulfate. Then, the solvent wasevaporated under reduced pressure to yield 1.25 g of yellow solid. Thesolid was purified with a silica gel column (hexane/ethyl acetate=7/3)to yield 0.46 g of the compound of the heading (yield: 22%).

¹H-NMR (CDCl₃) δ ppm: δ 2.00-2.15 (m, 2H), 2.70-3.10 (m, 4H), 3.75 (S,3H), 5.12 (m, 1H), 6.46 (s, 1H), 6.70 (d, 1H), 6.98 (d, 1H), 7.80 (t,1H), 8.22 (d, 1H), 8.50 (d, 1H), 8.72 (s, 1H).

EXAMPLE 6 Preparation of (S)-7-methoxy-2-aminotetralin

In a 10 mL autoclave placed were 253.1 mg of(R)-7-methoxy-2-methanesulfonyloxytetralin (87.8% ee) separatelysynthesized according to Example 3 and 1.3 mL of methanol. After coolingthe mixture to −78° C., 2.37 g (139 equivalents) of liquid ammonia wasadded and the autoclave was sealed. The reaction mixture was stirred at95° C. (external temperature) for 6 hours, and then the autoclave wasopened at −78° C. After evaporating ammonia under reduced pressure atroom temperature, the pH of the reaction mixture was adjusted to 3 with3M hydrochloric acid, and then methanol was evaporated under reducedpressure. After adding ethyl acetate to the residue, the product wasextracted two times with 1 M hydrochloric acid. The extract was adjustedto pH 11 with a 30% sodium hydroxide solution and further subjected toextraction with ethyl acetate. The organic phase was washed with asaturated aqueous solution of sodium chloride and dried over anhydroussodium sulfate. Then, the solvent was evaporated under reduced pressureto yield 74 mg of the compound of the heading (yield: 42%; opticalpurity: 87.0% ee). The optical purity was determined by high performanceliquid chromatography (HPLC) after deriving methylcarbamate.

HPLC conditions:

Column used, Chiralcel OD

Mobile phase, hexane/isopropanol=9/1

Temperature, 30° C.; measuring wavelength, 254 nm; flow rate, 1.0 mL/min

¹H-NMR (CDCl₃) δ ppm: δ 1.50-1.65 (m, 1H), 1.95-2.05 (m, 1H), 2.50-2.60(m, 1H), 2.72-2.90 (m, 2H), 2.93-3.05 (m, 1H), 3.15-3.25 (m, 1H), 3.78(S, 3H), 6.60 (s, 1H), 6.70 (d, 1H), 7.00 (d, 1H).

EXAMPLES 7 TO 17 Preparation of (S)-7-methoxy-2-aminotetralin

In a 10 mL autoclave placed were 128 mg of(R)-7-methoxy-2-methanesulfonyloxytetralin (87.8% ee) and 0.7 mL of asolvent listed in Table 1. After cooling the mixture to −78° C., liquidammonia was added in an amount shown in Table 1 and the autoclave wassealed. The reaction mixture was stirred at a temperature shown in Table1 for 6 hours, and then the autoclave was opened at −78° C. Afterevaporating ammonia under reduced pressure at room temperature, the pHof the reaction mixture was adjusted to 3 with 3 M hydrochloric acid,and then methanol was evaporated under reduced pressure. After addingethyl acetate to the residue, the product was extracted two times with 1M hydrochloric acid. The extract was adjusted to pH 11 with a 30% sodiumhydroxide solution and further subjected to extraction with ethylacetate. The organic phase was washed with a saturated aqueous solutionof sodium chloride and dried over anhydrous sodium sulfate. Then, thesolvent was evaporated under reduced pressure to yield the compound ofthe heading in an amount shown in Table 1. The yield is shown inTable 1. TABLE 1 Temperature Example Solvent NH₃ (equivalent) (° C.)Yield 7 MeOH 166 150 46% 8 MeOH 263 95 41% 9 NaOH/toluene = 1/1 164 9553% 10 NaOH/water = 1/1 164 95 37% 11 nBuOH 177 95 53% 12 Toluene 156100 47% 13 DMF 168 75 50% 14 THF 210 100 51% 15 DME 200 100 51% 16Acetonitrile 164 100 50% 17 Triethylamine 162 100 51%

EXAMPLE 18 Preparation of (S)-7-methoxy-2-aminotetralin

In a 10 mL autoclave placed were 165.3 mg of(R)-7-methoxy-2-p-toluenesulfonyloxytetralin (87.8% ee) and 0.7 mL ofmethanol. After cooling the mixture to −78° C., 1.49 g (176 equivalents)of liquid ammonia was added and the autoclave was sealed. The reactionmixture was stirred at 95° C. (external temperature) for 6 hours, andthen the autoclave was opened at −78° C. After evaporating ammonia underreduced pressure at room temperature, the pH of the reaction mixture wasadjusted to 3 with 3 M hydrochloric acid, and then methanol wasevaporated under reduced pressure. After adding ethyl acetate to theresidue, the product was extracted two times with 1 M hydrochloric acid.The extract was adjusted to pH 11 with a 30% sodium hydroxide solutionand further subjected to extraction with ethyl acetate. The organicphase was washed with a saturated aqueous solution of sodium chlorideand dried over anhydrous sodium sulfate. Then, the solvent wasevaporated under reduced pressure to yield 42 mg of the compound of theheading (yield: 48%).

EXAMPLE 19 Preparation of (S)-7-methoxy-2-aminotetralin

In a 10 mL autoclave placed were 181.0 mg of(R)-7-methoxy-2-(3-nitrobenzenesulfonyloxy)tetralin (87.8% ee) and 0.7mL of methanol. After cooling the mixture to −78° C., 1.49 g (176equivalents) of liquid ammonia was added and the autoclave was sealed.The reaction mixture was stirred at 95° C. (external temperature) for 6hours, and then the autoclave was opened at −78° C. After evaporatingammonia under reduced pressure at room temperature, the pH of thereaction mixture was adjusted to 3 with 3 M hydrochloric acid, and thenmethanol was evaporated under reduced pressure. After adding ethylacetate to the residue, the product was extracted two times with 1 Mhydrochloric acid. The extract was adjusted to pH 11 with a 30% sodiumhydroxide solution and further subjected to extraction with ethylacetate. The organic phase was washed with a saturated aqueous solutionof sodium chloride and dried over anhydrous sodium sulfate. Then, thesolvent was evaporated under reduced pressure to yield 28 mg of thecompound of the heading (yield: 32%).

EXAMPLE 20 Preparation of (S)-7-methoxy-2-aminotetralin hydrochloride

Ethanol in an amount of 18.4 mL was added to 184 g of a mixed solutionof (S)-7-methoxy-2-aminotetralin (18.4 g, optical purity: 99.8% ee)separately synthesized according to Example 6 and toluene. While themixture was being stirred, 11.9 g of concentrated hydrochloric acid wasadded at an internal temperature of 25° C. over a period of 1.5 hours.The mixture was stirred at 25° C. for another one hour, and thenprecipitated crystals were filtrated. The collected wet crystals werewashed twice with 37 mL of toluene and dried to yield the crystals of(S)-7-methoxy-2-aminotetralin hydrochloride (17.6 g; yield: 83%; opticalpurity: 99.9% ee).

EXAMPLE 21 Preparation of (S)-7-methoxy-2-aminotetralin hydrochloride

To (S)-7-methoxy-2-aminotetralin hydrochloride (20.6 g, optical purity:99.9% ee) were added 20 mL of ethanol, 180 mL of toluene, and 7 mL ofwater, and the mixture was heated to dissolve the crystals. Afterstirring for 15 minutes, the solution was cooled to room temperature,and further cooled with ice. After stirring for 30 minutes, the crystalswere filtrated. The collected wet crystals were washed twice with 40 mLof toluene, and dried to yield the crystals of(s)-7-methoxy-2-aminotetralin hydrochloride (19.0 g; yield: 92%; opticalpurity: 99.9% ee).

EXAMPLE 22 Preparation of (S)-7-methoxy-2-aminotetralin hydrochloride

Concentrated hydrochloric acid in an amount of 63 mg was added to amixed solution of separately synthesized (S)-7-methoxy-2-aminotetralin(99.2 mg; optical purity: 91.2% ee) and 1 mL of ethanol at an internaltemperature of 25° C. while the mixture was being stirred. The mixturewas stirred at 25° C. for another one hour, and then precipitatedcrystals were filtrated. The collected wet crystals were washed withtoluene and dried to yield the crystals of (S)-7-methoxy-2-aminotetralinhydrochloride (76.2 mg; yield: 64%; optical purity: 95.5% ee).

EXAMPLE 23 Preparation of (S)-7-methoxy-2-aminotetralin hydrochloride

An isopropanol solution of hydrogen chloride (hydrogen chlorideconcentration: 34%) in an amount of 65 mg was added to a mixed solutionof (S)-7-methoxy-2-aminotetralin (102.1 mg; optical purity: 91.2% ee)and 1 mL of isopropanol at an internal temperature of 25° C. while themixture was being stirred. The mixture was stirred at 25° C. for anotherone hour, and then precipitated crystals were filtrated. The collectedwet crystals were washed with isopropanol and dried to yield thecrystals of (S)-7-methoxy-2-aminotetralin hydrochloride (76.2 mg; yield:63%; optical purity: 98.7% ee).

EXAMPLE 24 Preparation of (S)-7-methoxy-2-aminotetralin hydrochloride

The mixture of separately synthesized (S)-7-methoxy-2-aminotetralinhydrochloride (100.7 mg; optical purity: 93.0% ee) and 1 mL of ethanolwas heated to dissolve. The solution was cooled to room temperaturewhile being stirred. After being stirred for 1 hour, the solution wasstirred in an ice bath for another one hour. The precipitated crystalswere filtrated. The collected wet crystals were washed with toluene anddried to yield the crystals of (s)-7-methoxy-2-aminotetralinhydrochloride (69.2 mg; yield: 69%; optical purity: 99.3% ee).

EXAMPLE 25 Preparation of (S)-7-methoxy-2-aminotetralin hydrochloride

A mixture of (S)-7-methoxy-2-aminotetralin hydrochloride (100.4 mg;optical purity: 93.0% ee) and 1 mL of hydrated ethanol(ethanol:water=95:5 (on a volume basis)) was heated to dissolve. Thesolution was cooled to room temperature while being stirred, and furtherstirred for 0.5 hour. The precipitated crystals were filtrated. Thecollected wet crystals were washed with toluene and dried to yield thecrystals of (s)-7-methoxy-2-aminotetralin hydrochloride (50.6 mg; yield:50.4%; optical purity: 98.5% ee).

EXAMPLE 26 Preparation of (S)-7-methoxy-2-aminotetralin hydrochloride

The mixture of (S)-7-methoxy-2-aminotetralin hydrochloride (100.6 mg;optical purity: 93.0% ee) and 5 mL of isopropanol was heated todissolve. The solution was cooled to room temperature while beingstirred. After being stirred for 0.5 hour, the solution was stirred inan ice bath for another one hour. The precipitated crystals werefiltrated. The collected wet crystals were washed with isopropanol anddried to yield the crystals of (s)-7-methoxy-2-aminotetralinhydrochloride (51.0 mg; yield: 51%; optical purity: 99.3% ee).

EXAMPLE 27 Preparation of (S)-7-methoxy-2-aminotetralin hydrochloride

The mixture of (S)-7-methoxy-2-aminotetralin hydrochloride (100.6 mg;optical purity: 93.0% ee) and 1 mL of ethanol was heated to dissolve. Tothe solution was added 1 mL of diethyl ether while being stirred. Thesolution was cooled to room temperature and stirred for 0.5 hour. Theprecipitated crystals were filtrated. The collected wet crystals werewashed with diethyl ether and dried to yield the crystals of(s)-7-methoxy-2-aminotetralin hydrochloride (85.4 mg; yield: 85%;optical purity: 98.4% ee).

EXAMPLE 28 Preparation of (S)-7-methoxy-2-azidotetralin

DMSO in an amount of 15.0 mL was added to(R)-7-methoxy-2-methanesulfonyloxytetralin (261 mg, 1.018 mmol; opticalpurity: 87.8% ee) separately synthesized according to Example 3, and thereactor was purged with nitrogen. NaN₃ (purity: 90%; 740.3 mg, 10.20mmol, 10 equivalents) was added at room temperature, followed bystirring at 50° C. for 4 hours. After cooling, 15 mL of water was added,and the product was extracted two times with 20 mL of toluene. Theorganic phase was washed with 20 mL of water and 20 mL of brine andconcentrated to yield 195 mg of crude product. According to ¹H-NMR, thecrude product contained 92% of (S)-7-methoxy-2-azidotetralin and 8% of7-methoxy-3,4-dihydronaphthalene (yield of 7-methoxy-2-azidotetralin:88%).

¹H-NMR (CDCl₃) δ ppm: 1.83-1.91 (m, 1H), 2.08-2.11 (m, 1H), 2.73-2.92(m, 3H), 3.05 (dd, J=5.0, 16.4 Hz, 1H), 3.77 (s, 3H), 3.78-3.88 (m, 1H),6.61 (d, J=2.4 Hz, 1H), 6.72 (dd, J=2.4, 8.3 Hz, 1H), 7.01 (d, J=8.3 Hz,1H), 7.25 (s, 1H).

EXAMPLE 29 Preparation of (S)-7-methoxy-2-aminotetralin

A toluene solution containing 2.66 g of (S)-7-methoxy-2-azidotetralinprepared in Example 28 was cooled to 5° C., and then 0.27 g (10 percentby weight relative to the substrate) of hydrous Pd/C (water content: 50percent by weight) was added in an atmosphere of nitrogen. Then, theatmosphere in the vessel was replaced with a hydrogen atmosphere and thereaction mixture was stirred for 8 hours without changing temperature.After the reaction had been completed, the temperature is increased toroom temperature, and the Pd/C was removed by filtration under reducedpressure. The removed Pd/C was washed with 13 g of toluene. Thus, atoluene solution containing 2.17 g of (S)-7-methoxy-2-aminotetralin wasobtained (yield: 93%).

EXAMPLE 30 Preparation of (S)-7-methoxy-2-phthalimidotetralin

Phthalimide potassium salt (281 mg, 1.5 equivalents) was added to(R)-7-methoxy-2-methanesulfonyloxytetralin (265 mg, 1.03 mmol; opticalpurity: 87.8% ee) and 5 mL of DMF, and the reactor was purged withnitrogen. The reaction mixture was heated to 60° C. and allowed to reactfor 24 hours. After cooling, 15 mL of water was added, and the productwas extracted two times with 20 mL of toluene. The organic phase waswashed with 20 mL of water and 20 mL of brine and concentrated to yield410 mg of crude product. The crude product was purified by silica gelcolumn chromatography (eluent:hexane/ethyl acetate=2:1) to yield 85.4 mgof (S)-7-methoxy-2-phthalimidotetralin (yield: 27%).

¹H-NMR (CDCl₃) δ ppm: 1.95-2.03 (m, 1H), 2.63-2.94 (m, 3H), 3.62 (dd,J=12.0, 16.5 Hz, 1H), 3.79 (s, 3H), 4.58-4.63 (m, 1H), 6.63 (d, J=2.4Hz, 1H), 6.75 (dd, J=2.4, 8.3 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 7.25 (s,1H), 7.65-7.78 (m, 2H), 7.82-7.89 (m, 2H).

EXAMPLE 31 Preparation of (R)-7-methoxy-2-tetralol

In a test tube was placed 5 mL of liquid culture medium (pH 7.0) havingthe composition described in Example 1, and was steamsterilized at 120°C. for 20 minutes. A loopful of one of the microorganism listed in Table2 was aseptically inoculated into the culture, followed by shaking tocultivate the microorganism at 30° C. for 24 to 72 hours. After thecultivation, the culture broth was centrifuged to collect cells, and thecells were suspended in 1 mL of a 100 mM phosphate buffer solution (pH7.0). To this suspension were added 5 mg of 7-methoxy-2-tetralone and 5g of glucose, followed by stirring at 30° C. for 24 hours. Afterreaction, 5 mL of ethyl acetate was added to extract the product. Theorganic phase was analyzed by high performance liquid chromatography andmeasured the yield and the optical purity of the product(R)-7-methoxy-2-tetralol. The results are shown in Table 2. Thechromatography for calculating the yield was performed under thefollowing conditions, and the optical purity was measured in the samemanner as in Example 1.

Column: Nomura Chemical, Develosil ODS-HG3 (4.6 mm×150 mm);eluent:water/acetonitrile=2/1; flow rate: 0.7 mL/min; detection: 254 nm;column temperature: room temperature. TABLE 2 Yield OpticalMicroorganism (%) purity (% ee) Candida catenulata IFO 0745 14.9 33.1Candida glabrata IFO 0005 28.0 70.8 Candida maltosa IFO 1976 29.7 70.3Candida maris IFO 10003 41.1 34.2 Candida albicans IFO 1594 68.3 61.7Candida fennica CBS 6087 58.4 73.1 Debaryomyces hansenii var. hanseniiIFO 0019 10.6 53.1 Pichia anomala IFO 0118 44.6 52.5 Kluyveromycespolysporus IFO 0996 90.9 35.7 Metschnikowia bicuspidata var. IFO 140876.1 49.9 bicuspidata Ogataea minuta var. nonfermentans IFO 1473 30.652.5 Sporidiobolus johnsonii IFO 6903 31.8 88.1 Torulaspora delbrueckiiIFO 0381 19.5 47.7 Geotrichum fermentans IFO 1199 31.2 36.1 Yamadazymafarinosa IFO 0534 49.0 79.7

EXAMPLE 32 Preparation of (S)-7-methoxy-2-tetralol

Using the microorganisms listed in Table 3, the same operation asExample 31 was performed to prepare (S)-7-methoxy-2-tetralol. Theresults are shown in Table 3. TABLE 3 Optical Microorganism Yield (%)purity (% ee) Candida glaebosa IFO 1353 79.7 61.7 Candida haemulonii IFO10001 25.8 88.5 Candida holmii IFO 0660 34.7 37.3 Candida intermedia IFO0761 23.4 79.5 Candida boidinii IFO10240 14.5 39.1 Candida pintolopesiiIFO 0729 31.4 36.6 Candida oleophila IFO 1021 67.3 71.6 Candidasonorensis IFO 10027 16.5 32.3 Candida tropicalis IFO 0618 65.2 52.9Debaryomyces carsonii IFO 0946 46.1 83.1 Endomyces decipiens IFO 010216.8 79.3 Dipodascus ovetensis IFO 1201 55.6 93.9 Saccharomycopsisselenospora IFO 1850 56.1 44.7 Issatchenkia terricola IFO 0933 16.0 76.9Kuraishia capsulata IFO 0721 82.5 71.3 Lipomyces starkeyi IFO 0678 12.486.6 Lodderomyces elongisporus IFO 1676 38.8 61.5 Metschnikowia gruessiiIFO 0749 72.4 36.5 Pichia wickerhamii IFO 1278 36.9 69.1 Rhodosporidiumtoruloides IFO 0559 23.9 30.9 Rhodotorula araucariae IFO 10053 16.3 32.5Sporobolomyces salmonicolor IFO 1038 42.5 35.5 Sporidiobolus holsaticusIFO 1032 25.2 54.9 Debaryomyces occidentalis var. IFO 0371 20.5 58.2occidentalis Saturnispora dispora IFO 0035 21.2 70.9 Candida stellataIFO 0703 21.6 54.7 Zygosaccharomyces bailii IFO 0519 27.8 51.4Zygosaccharomyces bailii IFO 0488 34.5 44.5 Zygosaccharomyces bailii IFO0493 34.2 49.3

EXAMPLE 33 Preparation of (R)-7-methoxy-2-tetralol

In a test tube was placed 5 mL of liquid culture medium (pH 7.0)containing 10 g of polypeptone, 10 g of meat extract, and 5 g of yeastextract, and was steamsterilized at 120° C. for 20 minutes. A loopful ofone of the microorganism listed in Table 4 was aseptically inoculatedinto the culture medium, followed by shaking to cultivate themicroorganism at 30° C. for 24 hours. After cultivation, the culturebroth was centrifuged to collect cells and the cells were suspended in 1mL of a 100 mM phosphate buffer solution (pH 7.0). To this suspensionwere added 5 mg of 7-methoxy-2-tetralone and 5 g of glucose, followed bystirring at 30° C. for 24 hours. After reaction, 5 mL of ethyl acetatewas added to extract the product. The yield and the optical purity ofthe product (R)-7-methoxy-2-tetralol were measured in the same manner asin Example 31. The results are shown in Table 4. TABLE 4 Optical purityMicroorganism Yield (%) (% ee) Arthrobacter protophormiae IFO 12128 32.457.2 Acidiphilium cryptum IFO 14242 45.3 89.0 Pseudomonas putida IFO14164 26.8 92.1 Rhodococcus erythropolis IFO 12320 24.6 65.0 Devosiariboflavina IFO 13584 30.0 95.0

EXAMPLE 34 Preparation of (S)-7-methoxy-2-tetralol

Using the microorganisms listed in Table 5, the same operation asExample 33 was performed to prepare (S)-7-methoxy-2-tetralol. Theresults are shown in Table 5. TABLE 5 Yield Optical Microorganism (%)purity (% ee) Cellulomonas fimi IFO15513 68.6 66.1 Jensenia canicruriaIFO 13914 17.2 64.9 Micrococcus luteus IFO 13867 12.8 34.3 Rhodococcuserythropolis IAM 1474 66.2 76.4

EXAMPLE 35 Preparation of (R)-7-methoxy-2-tetralol

In a test tube was placed 5 mL of liquid culture medium (pH 7.0) havingthe composition described in Example 1, and was steamsterilized at 120°C. for 20 minutes. A loopful of Candida magnoliae IFO705 was asepticallyinoculated into the culture medium, followed by shaking to cultivate themicroorganism at 30° C. for 24 to 72 hours. After cultivation, theculture broth was centrifuged to collect cells, and the cells weresuspended in 50 mL of a 100 mM phosphate buffer solution (pH 7.0). Tothe suspension were added 1 g of 7-methoxy-2-tetralone bisulfite adductand 5 g of glucose. Then, the pH of the reaction mixture was maintainedat 6.5 with an aqueous solution of 5 M sodium hydroxide while thesolution was stirred at 30° C. for 24 hours. After the reaction had beencompleted, the reaction mixture was extracted two times with 500 mL ofethyl acetate. The organic phase was dried over anhydrous sodiumsulfate. The anhydrous sodium sulfate was removed by filtration, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to yield 450 mg of(R)-7-methoxy-2-tetralol (yield: 45%). The optical purity measured inthe same manner as in Example 1 was 81% ee.

REFERENCE EXAMPLE Preparation of 7-methoxy-2-tetralone bisulfite adduct

In 200 mL of methanol was dissolved 17.6 g of 7-methoxy-2-tetralone.While the solution was cooled with ice, 100 mL of 20% sodium bisulfitesolution was added to the solution, followed by stirring for 30 minutes.Precipitated white crystals were filtrated, and the product was driedunder reduced pressure to yield 19 g of the compound of the heading.

INDUSTRIAL APPLICABILITY

Since the present invention includes the above-described characteristicfeatures, an optically active 7-substituted-2-aminotetralin can beefficiently, easily, and industrially advantageously prepared from a7-substituted-2-tetralone.

1. A process for preparing an optically active 7-substituted-2-tetralolexpressed by general formula (2):

(wherein R₁ represents hydrogen, an alkyl group having 1 to 10 carbonatoms, an aryl group having 6 to 20 carbon atoms, or an aralkyl grouphaving 7 to 20 carbon atoms, and * represents an asymmetric carbonatom), comprising the step of reacting a 7-substituted-2-tetraloneexpressed by general formula (1):

(wherein R₁ represents the same as above) or a bisulfite adduct thereofwith a culture broth of microorganism, cells, or a material derivedtherefrom capable of transforming the 7-substituted-2-tetralone or thebisulfite adduct thereof into the optically active7-substituted-2-tetralol, wherein the microorganism is a microorganismbelonging to a genus selected from the group consisting of Candida,Debaryomyces, Pichia, Kluyveromyces, Metschnikowia, Ogataea,Sporidiobolus, Torulaspora, Geotrichum, Yamadazyma, Endomyces,Dipodascus, Saccharomycopsis, Issatchenkia, Kuraishia, Lipomyces,Lodderomyces, Rhodosporidium, Rhodotorula, Sporobolomyces, Saturnispora,Zygosaccharomyces, Cellulomonas, Jehsenia, Arthrobacter, Acidiphilium,Pseudomonas, Rhodococcus, Devosia, and Micrococcus.
 2. The processaccording to claim 1, wherein the 7-substituted-2-tetralone expressed byformula (1) or the bisulfite adduct thereof is reacted with a culturebroth of microorganism, cells, or a material derived therefrom capableof transforming the 7-substituted-2-tetralone or the bisulfite adductthereof into an optically active 7-substituted-2-tetralol having the (R)configuration to prepare the (R)-7-substituted-2-tetralol, and themicroorganism is a microorganism belonging to a genus selected from thegroup consisting of Candida, Debaryomyces, Pichia, Kluyveromyces,Metschnikowia, Ogataea, Sporidiobolus, Torulaspora, Geotrichum,Yamadazyma, Arthrobacter, Acidiphilium, Pseudomonas, Rhodococcus, andDevosia.
 3. The process according to claim 1, wherein the7-substituted-2-tetralone expressed by formula (1) or the bisulfiteadduct thereof is reacted with a culture broth of microorganism, cells,or a material derived therefrom capable of transforming the7-substituted-2-tetralone or the bisulfite adduct thereof into anoptically active 7-substituted-2-tetralol having the (S) configurationto prepare the (S)-7-substituted-2-tetralol, and the microorganism is amicroorganism belonging to a genus selected from the group consisting ofCandida, Debaryomyces, Endomyces, Dipodascus, Saccharomycopsis,Issatchenkia, Kuraishia, Lipomyces, Lodderomyces, Pichia,Rhodosporidium, Rhodotorula, Sporobolomyces, Sporidiobolus,Saturnispora, Zygosaccharomyces, Cellulomonas, Jensenia, Micrococcus,Rhodococcus, and Metschnikowia.
 4. The process according to claim 1,wherein the culture broth of microorganism, cells, or a material derivedtherefrom contains at least one microorganism selected from the groupconsisting of Candida magnoliae, Candida maris, Candida catenulate,Candida glabrata, Candida maltosa, Candida albicans, Candida fennica,Debaryomyces hansenii var. hansenii, Pichia anomala, Kluyveromycespolysporus, Metschnikowia bicuspidata var. bicuspidata, Ogataea minutavar. nonfermentans, Sporidiobolus johnsonii, Torulaspora delbrueckii,Geotrichum fermentans, Yamadazyma farinosa, Arthrobacter protophormiae,Acidiphilium cryptum, Pseudomonas putida, Rhodococcus erythropolis, andDevosia riboflavina.
 5. The process according to claim 1, wherein theculture broth of microorganism, cells, or a material derived therefromcontains at least one microorganism selected from the group consistingof Candida glaebosa, Candida haemulonii, Candida holmii, Candidaintermedia, Candida boidinii, Candida pintolopesii, Candida oleophila,Candida sonorensis, Candida tropicalis, Debaryomyces carsonii, Endomycesdecipiens, Dipodascus ovetensis, Saccharomycopsis selenospora,Issatchenkia terricola, Kuraishia capsulate, Lipomyces starkeyi,Lodderomyces elongisporus, Metschnikowia gruessii, Pichia wickerhamii,Rhodosporidium toruloides, Rhodotorula araucariae, Sporobolomycessalmonicolor, Sporidiobolus holsaticus, Debaryomyces occidentalis var.occidentalis, Saturnispora dispora, Candida stellata, Zygosaccharomycesbailii, Cellulomonasfimi, Jensenia canicruria, Micrococcus luteus, andRhodococcus erythropolis.
 6. The process according to claim 1, whereinR₁ represents a methyl group.
 7. A process for preparing an opticallyactive 7-substituted-2-aminotetralin expressed by general formula (5):

(wherein * represents an asymmetric carbon atom and R₁ representshydrogen, an alkyl group having 1 to 10 carbon atoms, an aryl grouphaving 6 to 20 carbon atoms, or an aralkyl group having 7 to 20 carbonatoms) or a salt thereof, comprising the steps of: introducing asulfonyl group to the hydroxy group of an optically active7-substituted-2-tetralol expressed by general formula (2):

(wherein * and R₁ represents the same as above) to form an opticallyactive 7-substituted-2-sulfonyloxytetralin expressed by general formula(3):

(wherein * and R₁ represent the same as above, and R₂ represents analkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20carbon atoms, an aralkyl group having 7 to 20 carbon atoms, asubstituted amino group, or a hydroxy group); introducing a nitrogensubstituent using a nitrogen nucleophile to form an optically active2,7-substituted tetralin expressed by general formula (4):

(wherein * and R₁ represents the same as above, and X represents anon-substituted amino group, an alkylamino group having 1 to 10 carbonatoms, an arylamino group having 6 to 20 carbon atoms, an aralkylaminogroup having 7 to 20 carbon atoms, an amido group having 1 to 20 carbonatoms, an imido group having 2 to 20 carbon atoms, a sulfonylamino grouphaving 1 to 20 carbon atoms, or an azido group) while the configurationis inversed; and, if necessary, transforming the nitrogen substituent toa non-substituted amino group.
 8. The process according to claim 7,wherein an (S)-7-substituted-2-aminotetralin (5) is prepared from an(R)-7-substituted-2-tetralol (2).
 9. The process according to claim 7,wherein the optically active 7-substituted-2-tetralol (2) is prepared bythe process comprising the step of reacting a 7-substituted-2-tetraloneexpressed by general formula (1):

(wherein R₁ represents the same as above) or a bisulfite adduct thereofwith a culture broth of microorganism, cells, or a material derivedtherefrom capable of transforming the 7-substituted-2-tetralone or thebisulfite adduct thereof into the optically active7-substituted-2-tetralol, wherein the microorganism is a microorganismbelonging to a genus selected from the group consisting of Candida,Debaryomyces, Pichia, Kluyveromyces, Metschnikowia, Ogataea,Sporidiobolus, Torulaspora, Geotrichum, Yamadazyma, Endomyces,Dipodascus, Saccharomycopsis, Issatchenkia, Kuraishia, Lipomyces,Lodderomyces, Rhodosporidium, Rhodotorula, Sporobolomyces, Saturnispora.Zygosaccharomyces, Cellulomonas, Jensenia, Arthrobacter, Acidiphilium,Pseudomonas, Rhodococcus, Devosia, and Micrococcus.
 10. The processaccording to claim 7, wherein the nitrogen nucleophile is ammonia, ametal salt of a phthalimide, or a metal azide, and X in general formula(4) is an amino group, a phthalimido group, or an azido group.
 11. Theprocess according to claim 10, wherein the nitrogen nucleophile isammonia, and X is an amino group.
 12. The process according to claim 7,wherein the nitrogen nucleophile is a metal azide, and X is an azidogroup, and wherein the 2,7-substituted tetralin expressed by generalformula (4) is transformed to the optically active2-substituted-2-aminotetralin expressed by general formula (5) or a saltthereof by reduction.
 13. The process according to claim 12, whereinhydrogen is used in the reduction.
 14. An optically active7-substituted-2-sulfonyloxytetralin expressed by general formula (3):

(wherein * represents an asymmetric carbon atom, and R₁ representshydrogen, an alkyl group having 1 to 10 carbon atoms, an aryl grouphaving 6 to 20 carbon atoms, or an aralkyl group having 7 to 20 carbonatoms, and R₂ represents an alkyl group having 1 to 10 carbon atoms, anaryl group having 6 to 20 carbon atoms, an aralkyl group having 7 to 20carbon atoms, a substituted amino group, or a hydroxy group).
 15. Acompound according to claim 14, wherein R₁ is a methyl group.
 16. Acompound according to claim 14, wherein R₂ is a methyl group, a phenylgroup, a p-methylphenyl group, an o-nitrophenyl group, a m-nitrophenylgroup, or a p-nitrophenyl group.